It is known that certain mevalonate derivatives inhibit the biosynthesis of cholesterol, c.f. F. M. Singer et al, Proc. Soc. Exper. Biol. Med., 102 370 (1959) and F. H. Hulcher, Arch. Biochem. Biophys., 146, 422 (1971). Nevertheless, the activity of these known compounds has not always been found to be satisfactory, i.e. to have practical application.
Recently, Endo et al, reported (U.S. Pat. Nos. 4,049,495, 4,137,322 and 3,983,140) the production of fermentation products which were quite active in the inhibition of cholesterol biosynthesis. The most active member of this group of natural products, now called compactin, IIIa(R'=H) was reported by Brown et al. [J. Chem. Soc. Perkin I 1165 (1976)] to have a complex mevalonolactone structure.
More recently, Monaghan et al in U.S. Pat. No. 4,231,938, which is incorporated herein by reference, reported an inhibitor, designated MK-803 and having the structure III.sub.a (R'=CH.sub.3) in Table I, which was isolated from an entirely different fermentation. Albers-Schonberg et al (U.S. Pat. No. 4,294,846) described a dihydro MK-803, designated III.sub.d (R'=CH.sub.3) in Table I, of about equal potency to MK-803 isolated from the same fermentation as was MK-803. Patchett et al (U.S. Ser. No. 210,826, filed Dec. 1, 1980) describe dihydro and tetrahydro derivatives of MK-803 of different structures (III.sub.b,c and e (R'=CH.sub.3) in Table I), prepared by the catalytic hydrogenation of MK-803. Willard (U.S. Pat. No. 4,293,496), describes the preparation of the 8-hydroxy derivatives (IV.sub.a-e (R'=CH.sub.3) in Table I) which are the starting materials for the preparation of some of the novel compounds of this invention.
A tetrahydro analog III.sub.e (R'=H), of compactin was reported in published Japanese Application (Kokai) 55009-024.
Very recently a dihydro-analog of compactin of structure III.sub.d (R=H) was isolated from compactin fermentation broths as reported by Gullo et al, (U.S. application Ser. No. 207,508, filed Nov. 17, 1980).
The preparation of the starting material, III.sub.d, R.sup.1 =CH.sub.3) as mentioned previously, is described by Albers-Schonberg et al in U.S. Pat. No. 4,294,846, and is the product of the following fermentation with a strain of Aspergillus terreus, ATCC No. 20542, designated MF-4845 in the culture collection of MERCK & CO., Inc., Rahway, N.J.